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Development of the peritoneal cavity, gastrointestinal tract and its adnexae
Postpharyngeal Foregut
The primitive gut is divided by head- and tail-folding into three main compartments. The foregut extends from the buccopharyngeal membrane to its continuation into the central midgut region via the cranial intestinal portal. The midgut extends between the intestinal portals and, in the early embryo, is in wide communication with the yolk sac. The hindgut extends from the caudal intestinal portal to the cloacal membrane. The cranial end of the foregut, the embryonic pharynx, is intimately associated with head and neck development ( Ch. 17 ). The portion of foregut that passes dorsal to the pericardial cavity gives rise to the respiratory diverticulum and oesophagus within the thorax ( Chs 17 and 20 ). Caudal to the developing respiratory diaphragm, the enteric gut is conventionally subdivided into three embryological portions: fore-, mid- and hindgut. There are no corresponding fundamental morphological and cytological distinctions between the three parts ( Fig. 21.1 ), and so the foregut produces a portion of the duodenum, as does the midgut, and the midgut similarly produces large intestine, as does the hindgut. The differences between the portions of the gut develop as a result of interactions between the three embryonic tissue layers that give rise to the gut: namely, the endodermal inner epithelium, the thick layer of splanchnopleuric mesenchyme and the outer layer of proliferating splanchnopleuric coelomic epithelium.
The mucosal epithelial layer and connected ducts and glands are derived from the endodermal epithelium. The lamina propria and muscularis mucosa, the connective tissue of the submucosa, the muscularis externa and the future serosal lamina propria are all derived from the splanchnopleuric mesenchyme. The outer splanchnopleuric coelomic epithelium forms the epithelial component of the serosa (peritoneum, a mesothelium). Both epithelia, inner and outer, express cell polarity markers and form specific apical junctional complexes; they are highly proliferative and appear histologically as pseudostratified epithelia with interkinetic nuclear migration matching the timing of the cell cycle. In the endodermal layer, this proliferation results in lengthening of the inner endodermal epithelium. In the splanchnic coelomic epithelium, which acts as a barrier throughout development to contain locally secreted morphogens, proliferation not only increases the surface area and gives rise to the subjacent mesenchymal population, but also generates biomechanical tension across the whole composite tube, which by differentiative temporo-spatial patterning contributes to regional gut development ( , , , ).
Throughout the gut, blood vessels, lymphatics and lymph nodes develop from local populations of angiogenic mesenchyme. The nerves, which are distributed within the enteric and autonomic systems, are derived from the neural crest. There is a craniocaudal developmental gradient along the gut, in that the stomach and small intestine develop in advance of the colon.
Fig. 21.1 shows the fundamental relationship of the intraembryonic coelom to the developing gut. Fig. 21.2 shows the gut in a stage 12 embryo in relation to the other developing viscera, especially the heart and liver. Fig. 21.3 shows the overall development of the gut from stages 13 to 17. These diagrams should be compared. See Fig. 23.3 for a comparison of stages to postfertilzation days and the clinical scale of postmenstrual weeks.
All regions of the gut develop from epithelial–mesenchymal interactions that are dependent on the sequential expression of a range of basic and specific genes; on the regulation of the developmental clock, seen in all areas of development; and on endogenous regulatory mechanisms and local environmental influences ( ). Although all these factors pertain to the whole range of developing tissues, local differences in any one of these factors along the length of the developing gut promote the differentiation of, for example, the gastric mucosa and hepatocytes; the rotation of the midgut; and the final disposition of the sessile portions of the fully formed gastrointestinal tract. The Hedgehog (Hh) ligands, Shh, Ihh and Dhh, are expressed in the developing gut: Shh and Ihh in the endodermal epithelium and Dhh in endothelial cells. These ligands bind to the Patched receptors (Ptch-1 and Ptch-2), which activate the transcription factor Gli3. Knockout of Shh and Ihh has been associated with oesophageal atresia, gut malrotation, decreased development of the muscularis propria, enteric neurone anomalies and imperforate anus ( ). The gut is functional prior to birth and able to interact with the extrauterine environment in preterm infants.
Oesophagus
The oesophagus can be distinguished from the stomach at stage 13 (31–33 days postfertilization). It elongates during successive stages and its absolute length increases more rapidly than the embryo as a whole. By stage 15 it is surrounded by splanchnopleuric mesenchyme derived from the walls of the pericardioperitoneal canals. Cranially, it is dorsal to the developing trachea and the two tubes share the mesenchymal population between them; more caudally it is medial to the developing lung buds ( Fig. 21.3 ). The terminal, pregastric segment of the oesophagus is surrounded ventrally by the most cranial part of the septum transversum mesenchyme and dorsally by splanchopleuric mesenchyme, which forms a short, thick, dorsal meso-oesophagus with the lower medial walls of the pericardioperitoneal canals. Caudally these mesenchymal populations are continuous with their respective primitive dorsal and ventral mesogastria. Although the oesophagus has only limited areas related to a primary coelomic epithelium at its caudal end, it is important to note the subsequent development of the para-oesophageal right and left pneumatoenteric recesses (see Fig. 21.7 ), the relation of the ventral aspect of the middle third of the oesophagus to the oblique sinus of the pericardium, and the relation of its lateral walls in the lower thorax to the mediastinal pleura. All the foregoing are secondary extensions from the primary coelom.
The oesophageal mucosa consists of two layers of cells by stage 15, but the proliferation of the mucosa does not occlude the lumen at any time. The mucosa becomes ciliated at 10 postfertilization weeks, and stratified squamous epithelium is present after postmenstrual week 20; occasionally, patches of ciliated epithelium may be present at birth. Circular muscle can be seen at stage 15 but longitudinal muscle has not been identified until stage 21. Neuroblasts can be demonstrated in the early stages; the myenteric plexuses have cholinesterase activity by 9.5 postfertilization weeks and ganglion cells are differentiated by 13 postfertilization weeks. It has been suggested that the oesophagus is capable of peristalsis in the first trimester. Pharyngeal phase swallowing activity has been identified from 11 postmenstrual weeks on ultrasound examination; oesophageal motor function is well developed by 26 postmenstrual weeks ( , ). The volume of amniotic fluid ingested increases during the third trimester to more than 500 ml/day.
Oesophagus at birth
At birth, the oesophagus extends 8–10 cm from the cricoid cartilage to the gastric cardiac orifice. It starts and ends one to two vertebrae, respectively, higher than in the adult, extending from between the fourth to the sixth cervical vertebra to the level of the ninth thoracic vertebra (see Fig. 23.15 ). Its average diameter is 5 mm and it possesses the constrictions seen in the adult. The narrowest constriction is at its junction with the pharynx, where the inferior pharyngeal constrictor functions to constrict the lumen; this region may be easily traumatized with instruments or catheters. In the neonate, the mucosa may contain scattered areas of ciliated columnar epithelium but these disappear soon after birth. Complex swallowing and oesophageal reflexes are present in the full-term neonate ( Ch. 14 ). A coordinated relaxation of the upper oesophageal sphincter is followed sequentially by oesophageal peristalsis and relaxation of the lower oesophageal sphincter ( ). Air or liquid can be distinguished in the oesophagus and result in different swallowing patterns. Maturational changes are seen in the lower oesophageal sphincter relaxation reflex in the postnatal development of preterm infants ( ). In term and preterm infants, transient lower oesophageal sphincter relaxations, unrelated to swallowing, permit gastro-oesophageal reflux resulting in frequent regurgitation of food in the newborn period, with a peak prevalence at 4 postnatal months, declining thereafter ( ).
Stomach
The stomach can be recognized, at stage 13, as a fusiform dilation cranial to the wide opening of the midgut into the yolk sac (see Fig. 21.3 ). By stage 14 this opening has narrowed into a tubular vitelline intestinal duct, which will lose its connection with the digestive tube. At this time, the stomach is median in position and separated cranially from the pericardium by the septum transversum (see Fig. 21.5A ), which extends caudally on to the cranial side of the vitelline intestinal duct and ventrally to the somatopleure. Dorsally, the stomach is related to the aorta and connected to the body wall by a short dorsal mesentery, the dorsal mesogastrium, formed by the medial walls of the pleuroperitoneal canals and intervening splanchnopleuric mesenchyme (see Figs 21.5B , 21.6 ). The latter is directly continuous with the dorsal mesentery (mesenteron) of almost all of the remainder of the intestine, except its caudal short segment.
The characteristic gastric curvatures are already recognizable in human embryos during stages 15–16. Growth is more active along the dorsal border of the viscus; its convexity markedly increases and the rudimentary fundus appears. Because of more rapid growth along the dorsal border, the pyloric end of the stomach turns ventrally and the concave lesser curvature becomes apparent (see Figs 21.3 , 21.6 ). The stomach is now displaced to the left of the median plane and becomes physically rotated, such that its original right surface becomes dorsal and its left surface becomes ventral. Accordingly, the right vagus nerve is distributed mainly to the dorsal, and the left vagus mainly to the ventral, surfaces of the stomach. The dorsal mesogastrium increases in depth and becomes folded on itself. The ventral mesogastrium becomes more coronal than sagittal. The pancreaticoenteric recess (see Fig. 21.7B(ii) ), until this point conventionally described as a simple depression on the right side of the dorsal mesogastrium, becomes dorsal to the stomach and excavates downwards and to the left between the folded layers: it may now be termed the inferior recess of the bursa omentalis. To summarize, the stomach has undergone relative morphological movements, traditionally referred to as two ‘rotations’. The first is 90° clockwise, about a longitudinal axis viewed from the cranial end; the second is 90° clockwise, about a dorsoventral axis viewed ventrally. The displacement, morphological changes and apparent ‘rotation’ of the stomach have been attributed to differential growth changes of the stomach itself; extension of the pancreaticoenteric recess with changes in its mesenchymal walls; and pressure, particularly that exerted by the rapidly growing liver. Whether the ‘rotations’, which are conventionally used to aid understanding, occur only in the axes described is unclear; differential regional growth and some ‘rotation’ in the transverse plane have also been invoked. The angula insura and the cardia of the stomach can be seen in stage 18 and the fundus, body and pylorus are evident at stage 20 ( ).
Mucosa
Mucosal and submucosal development can be seen in postfertilization weeks 8–9. No villi form in the stomach, unlike in the small intestine; instead, glandular pits can be seen in the body and fundus. These develop in the pylorus and cardia by postfertilization weeks 10–11, when parietal cells can be demonstrated. Although the embryo generally matures in a proximo-distal direction, gastric glands form slightly later than villi in the midgut. Murine embryos show a sharp boundary between the mucosal epithelium of the stomach and the first duodenal crypt. It is suggested that repression of the determination of the stomach endodermal epithelium until a later time, when instructive signals from the surrounding mesenchyme specify a glandular rather than villous mucosal fate, could be part of the patterning of the pylorus and the first part of the duodenum ( ).
Chief cells can be identified after postfertilization weeks 12–13, although pepsinogen has not been demonstrated until term (40 postmenstrual weeks). Mucous neck cells actively produce mucus from 16 postmenstrual weeks. Acid secretion has not been demonstrated in the fetal stomach before 32 postmenstrual weeks, however, preterm infants from 26 postmenstrual weeks onwards, are able to secrete acid soon after birth. Intrinsic factor, also from parietal cells, has been detected after postfertilization week 11; it increases during postmenstrual weeks 14–15, at which time the pylorus, which contains more parietal cells than it does in the adult, also contains a relatively larger quantity of intrinsic factor. The significance of the early production of intrinsic factor and the late production of acid by the parietal cells is not known. Gastrin-producing cells have been demonstrated in the antrum between postmenstrual weeks 19 and 20, and gastrin levels have been measured in cord blood and in the plasma at term. Cord serum contains gastrin levels 2–3 times higher than those in maternal serum. Smooth muscle cells of the muscularis mucosae are first visible by 14 postmenstrual weeks and this layer is well defined by 22 postmenstrual weeks.
Muscularis
The muscularis externa can initially be seen at 10 postmenstrual weeks, when neural plexuses are developing in the body and fundus. At postmenstrual week 16, the oblique muscle layer can be seen and by postmenstrual week 26 all three muscularis externa layers are present. The pyloric musculature is thicker than that of the rest of the stomach; its layers develop within the same timescale as those in the fundus, cardia and body ( ).
Serosa
The serosa of the stomach is derived from the splanchnopleuric coelomic epithelium. No part of this serosa undergoes absorption. The original left side of the gastric serosa faces the greater sac; the right side faces the lesser sac.
Stomach at birth
The stomach exhibits fetal characteristics until just after birth, when the initiation of pulmonary ventilation, the reflexes of coughing and swallowing, and crying cause the ingestion of large amounts of air and liquid. Once postnatal swallowing has started, the stomach expands to four or five times its contracted state, and shifts its relative position accommodating the status of expansion and contraction of the other abdominal viscera, and to the position of the body. Gastric emptying is slower in the preterm infant than in the term infant ( ). In the neonate, the anterior surface of the stomach is generally covered by the left lobe of the liver, which extends nearly as far as the spleen (see Fig. 23.14B ). Only a small portion of the greater curvature of the stomach is visible anteriorly. The capacity of the stomach is 30–35 ml in the full-term neonate, rising to 75 ml in the second postnatal week and 100 ml by the fourth postnatal week (adult capacity is, on average, 1000 ml). The mucosa and submucosa are relatively thicker than in the adult; however, the muscularis is only moderately developed and peristalsis is not coordinated. At birth, gastric acid secretion is low, which means that gastric pH is high for the first 12 postnatal hours. It falls rapidly with the onset of gastric acid secretion, usually after the first feed. Acid secretion usually remains low for the first 10 postnatal days. Gastric emptying and transit times are delayed in the neonate.
Duodenum
The duodenum develops from the caudal part of the foregut and the cranial part of the midgut. A ventral mesoduodenum, which is continuous cranially with the ventral mesogastrium, is attached only to the foregut portion. Posteriorly, the duodenum has a thick dorsal mesoduodenum, which is continuous with the dorsal mesogastrium cranially and the dorsal mesentery of the midgut caudally. Anteriorly, the extreme caudal edge of the ventral mesentery of the foregut extends on to the short initial segment of the duodenum. The liver arises as a diverticulum from the ventral surface of the duodenum at the foregut–midgut junction, i.e. where the midgut is continuous with the yolk sac wall (the cranial intestinal portal). The ventral pancreatic bud also arises from this diverticulum. The dorsal pancreatic bud evaginates posteriorly into the dorsal mesoduodenum slightly more cranially than the hepatic diverticulum. The rotation, differential growth, and cavitations related to the developing stomach and omenta cause corresponding movements in the duodenum, which forms a loop directed to the right, with its original right side now adjacent to the posterior abdominal wall (see Fig. 21.6 ). This shift is compounded by the migration of the bile duct and ventral pancreatic duct around the duodenal wall. Their origin shifts until it reaches the medial wall of the second part of the fully formed duodenum; the bile duct passes posteriorly to the duodenum and travels in the free edge of the ventral duodenum and ventral mesogastrium. Local adherence of part of the duodenal serosa and the parietal peritoneum result in almost the whole of the duodenum, other than a short initial segment, becoming sessile.
Foregut anomalies
Oesophageal atresia is one of the more common obstructive conditions of the alimentary tract and may be indicated by polyhydramnios. It may be related to trachea-oesophageal fistulae or other associations of vertebral defects, anal atresia, cardiac defects, renal and limb anomalies (VACTERL) ( Ch. 20 ). Infantile hypertrophic pyloric stenosis has a prevalence of 2/1000 live births, with male sex and a family history being the most common associations. It presents between 3 to 8 postnatal weeks with projectile vomiting of milk feeds. Risk factors are first born, caesarean section delivery, preterm birth, formula feeding in the neonatal period; exclusive breast-feeding is noted to be protective ( ). No clear aetiology has been found, however the transition from a fetal gut receiving only amniotic fluid, with immature parietal cell function and neutral gastric pH, plus slow maturation of gastrin feedback mechanisms, is suggested to contribute to acid over secretion which stimulates pyloric sphincter hypertrophy ( ). Duodenal atresia is a developmental defect found in 1 in 5000 live births ( ). It may be associated with an anular pancreas, which may compress the duodenum externally (20% of duodenal atresia), or with anomalies of the bile duct. In 40–60% of cases, the atresia is complete and pancreatic tissue fills the lumen. The condition can be diagnosed on abdominal X-ray and ultrasound examination, which reveal a typical double bubble appearance, caused by fluid antenatally and air postnatally enlarging the stomach and the proximal duodenum. Polyhydramnios is invariably present and often is the indication for the scan. Duodenal atresia commonly occurs with other developmental defects, e.g. cardiac and skeletal anomalies, and in Down’s syndrome.
Special glands of the postpharyngeal foregut
Pancreas
The pancreas develops from two evaginations of the foregut that fuse to form a single organ. A dorsal pancreatic bud can be seen in stage 13 embryos as a thickening of the endodermal tube that proliferates into the dorsal mesogastrium (see Fig. 21.3 ; Fig. 21.4 ). A ventral pancreatic bud evaginates in close proximity to the liver primordium but cannot be clearly identified until stage 14, when it appears as an evagination of the bile duct itself. At stage 16 differential growth of the wall of the duodenum results in movement of the ventral pancreatic bud and the bile duct to the right side and, ultimately, to a dorsal position. It is not clear whether there is a corresponding shift of mesenchyme during this rotation. However, the ventral pancreatic bud and the bile duct rotate from a position within the ventral mesogastrium (ventral mesoduodenum) to one in the dorsal mesogastrium (dorsal mesoduodenum), which is destined to become fixed on to the posterior abdominal wall. By stage 17 the ventral and dorsal pancreatic buds have fused, although the origin of the ventral bud from the bile duct is still obvious. Three-dimensional reconstruction of the ventral and dorsal pancreatic buds has confirmed that the dorsal pancreatic bud forms the anterior part of the head, the body and the tail of the pancreas, and the ventral pancreatic bud forms the posterior part of the head and the posterior part of the uncinate process. The ventral pancreatic bud does not form all of the uncinate process ( ).
The developing pancreatic ducts usually fuse in such a way that most of the dorsal duct drains into the proximal part of the ventral duct (see Figs 21.3 – 21.4 ). The proximal portion of the dorsal duct usually persists as an accessory duct. The fusion of the ducts takes place late in development or in the postnatal period; 85% of infants have patent accessory ducts, as compared to 40% of adults. Fusion may not occur in 10% of individuals, in which case separate drainage into the duodenum is maintained: so-called pancreatic divisum (pancreas divisum). Failure of the ventral pancreatic diverticulum to migrate will result in an anular pancreas, which may constrict the duodenum locally.
Developmental movements of the pancreas in the dorsal mesoduodenum and dorsal mesogastrium are considered below (see p. 338 ).
Cellular development of the pancreas
The early specification of pancreatic endoderm requires the proximity of the notochord to the dorsal endoderm, which locally represses the expression of Shh transcription factor. Endoderm caudal to the pancreatic region does not respond to notochordal signals. The ventral pancreatic endoderm does not seem to undergo the same induction. Expression of pancreatic duodenal homeobox 1 transcription factor (PDX-1) is seen in the developing endodermal epithelial cells and in the maturing postnatal pancreas ( , ). Pancreatic mesenchyme is derived from two regions. The mesenchyme that surrounds the dorsal pancreatic bud proliferates from the splanchnopleuric coelomic epithelium of the medial walls of the pericardioperitoneal canals, whereas the ventral pancreatic bud is invested by septum transversum mesenchyme and by mesenchyme derived from the lower ventral walls of the pericardioperitoneal canals.
The primitive endodermal ductal epithelium provides the stem cell population for all the secretory cells of the pancreas. Initially, endocrine cells are located in the duct walls or in buds developing from them; later, they accumulate in pancreatic islets. The remaining primitive duct cells will differentiate into definitive ductal cells. In the fetus, they develop microvilli and cilia but lack the lateral interdigitations seen in the adult. Branches of the main duct become interlobular ductules, which terminate as blind-ending acini or as tubular, acinar elements.
The ductal branching pattern and acinar structure of the pancreas are determined by the pancreatic mesenchyme derived from the coelomic epithelium ( , ). This mesenchyme gives rise to connective tissue between the ducts, which, in the fetus, appears to be important in stimulating pancreatic proliferation and maintaining the relative proportions of acinar, α and β cells during development. It also provides cell lines for smooth muscle within the pancreas. Angiogenic mesenchyme invades the developing gland to produce blood and lymphatic vessels. Mouse pancreas endoderm grown in culture without coelomic epithelium does not show normal branching morphogenesis and exhibits higher endocrine/acinar pancreatic markers ( ).
The process of islet differentiation is divided into two phases ( ). Phase I, characterized by proliferation of polyhormonal cells, occurs from postmenstrual week 9 to week 15. Phase II, characterized by differentiation of monohormonal cells, is seen from postmenstrual week 16 onwards. The β cells, producing insulin and amylin, differentiate first, followed by α cells, which produce glucagon. The δ cells, which produce somatostatin, are seen after 30 postmenstrual weeks. The dorsal bud gives rise mostly to α cells, and the ventral bud to most of the pancreatic polypeptide-producing cells. The β cells develop from the duct epithelium throughout development and into the neonatal period. Later, in postmenstrual weeks 10–15, some of the primitive ducts differentiate into acinar cells, in which zymogen granules or acinar cell markers can be detected at 12–16 postmenstrual weeks.
The role of the medial coelomic walls of the lower ends of the pleuroperitoneal canals in pancreatic development has other interesting aspects, beyond that of a proliferative epithelium. This specific portion of coelomic epithelium forms tight junctions with adjacent cells and a basement membrane with the underlying mesenchyme, suggesting that it may function as a barrier preventing loss of intrapancreatic morphogens outwards and spread of extrapancreatic morphogens, e.g. from the mesenchyme surrounding the aorta, inwards, maintaining a boundary function between adjacent viscera ( ). This has been demonstrated in vitro using mouse embryonic tissue. Developing pancreatic and lung buds from which the coelomic epithelium had been removed fused into a single chimeric tissue mass, whereas no fusion occurred if the coelomic epithelium remained intact. When pancreas without coelomic epithelium was co-cultured with pancreas with intact coelomic epithelium, the epithelium engulfed both explants, extending over the entire surface, forming a larger pancreas. This is reminiscent of the process of dorsal and ventral pancreatic bud fusion. Fusion does not occur in co-culture of lung and pancreatic buds, or two pancreatic buds, when they are surrounded by the relevant coelomic epithelia ( ). This suggests that the maturing coelomic epithelium creates region-specific barriers between portions of gut and its evaginations with two distinct functions: maintenance of local internal environments which express specific and different morphogenetic molecules and maintenance of a barrier, ensuring lack of fusion, between closely apposed regions of gut and developing derived viscera.
Pancreas at birth
The pancreas in the neonate has all of the normal subdivisions of the adult. The pancreatic head is proportionately large in the newborn and there is a smooth continuation between the body and the tail. The inferior border of the head of the pancreas is found at the level of the second lumbar vertebra. The body and tail pass cranially and to the left, and the tail is in contact with the spleen.
Liver
The liver develops from an endodermal evagination of the foregut and from septum transversum mesenchyme, which is derived from the proliferating coelomic epithelium in the protocardiac region. The development of the liver is intimately related to the development of the heart. The vitelline veins, succeeded by the umbilical veins passing to the sinus venosus, are disrupted by the enlarging septum transversum to form a hepatic plexus, the forerunner of the hepatic sinusoids. (See for a detailed account of hepatic development.)
Early liver development
As the head fold and early intraembryonic coelom form, the ventral parietal wall of the pericardial cavity gives rise to populations of cells termed precardiac or cardiac mesenchyme. Hepatic endoderm is induced to proliferate by this mesenchyme, although all portions of the early heart tube, truncus arteriosus, atria, ventricle, both endocardium and myocardium, have hepatic induction potency that is tissue-specific but not species-specific. As the heart and foregut become separated by the accumulation of the cardiac mesenchyme, the mesenchyme itself is renamed septum transversum. It is seen as a ventral mass, caudal to the heart, which passes dorsally on each side of the developing gut to join the mesenchyme proliferating from the walls of the pericardioperitoneal canals. The majority of the cells within the septum transversum are destined to become hepatic mesenchyme. For details of the molecular signalling of early hepatic development, see , .
In the stage 11 embryo, the hepatic endoderm is located at the superior boundary of the rostral intestinal portal. By stage 12 the hepatic endodermal primordium is directed ventrally and begins to proliferate as a diverticulum. There are two parts: a caudal part, which will produce the cystic duct and gallbladder; and a cranial part, which forms the liver biliary system (see Fig. 21.3 ; Fig. 21.5A ). The cells start to express liver-specific molecular markers and glycogen storage.
The basal lamina around the cranial portion of the hepatic diverticulum is progressively disrupted and individual epithelial cells migrate into the surrounding septum transversum mesenchyme. The previously smooth contour of the diverticulum merges into columnar extensions of endoderm, the epithelial trabeculae, which stimulate the hepatic mesenchymal cells to form blood islands and endothelium. The advance of the endodermal epithelial cells promotes the conversion of progressively more hepatic mesenchyme into endothelium and blood cells, and only a little remains to form the scanty liver capsule and interlobular connective tissue. This invasion by the hepatic epithelium is completed in stage 13, when it approaches the caudal surface of the pericardial cavity from which it is separated by only a thin lamina of mesenchyme that will give rise to part of the respiratory diaphragm.
During this early phase of development, the liver is far more highly vascularized than the rest of the gut. The hepatic capillary plexus is connected bilaterally with the right and left vitelline veins. Dorsolaterally, these veins empty by multiple channels into enlarged hepatocardiac channels, that lead to the right and left horns of the sinus venosus (see Fig. 13.20 ); usually, the channel on the right side is more developed. Both left and right channels bulge into the pericardioperitoneal canals, forming sites for the exchange of fluid from the coelom into the vascular channels. The ingrowths of hepatic tissue in these regions are sometimes referred to as the left and right horns of the liver.
The liver remains proportionately large during its development and constitutes a sizeable organ dorsal to the heart at stage 14, then more caudally placed by stage 16. By this stage, hepatic ducts can be seen separating the hepatic epithelium from the extrahepatic biliary system, but, even at stage 17, the ducts do not penetrate far into the liver. The definitive arrangement of the portal and hepatic veins becomes established over stages 18–20. The quadrate and caudate lobes become identifiable in stages 16 and 17 ( ).
Maturation of the liver
The cellular maturation of hepatocytes and hepatic sinusoids corresponds to a complex cell sorting of early endodermal epithelial hepatoblasts, which differentiate into cholangiocytes and hepatocytes, angiogenic mesenchyme from the heart and developing gut which becomes organized into hepatic sinusoids, and septum transversum mesenchymal cells which give rise to the fibroblastic populations, and are thought to control the patterning of liver development with the angiogenic mesenchyme. The cellular arrangements within the liver are complex with sheets of epithelial hepatocytes, with apical biliary canaliculi between adjacent cells, arranged adjacent to sinusoids conveying portal and arterial blood to central veins. Epithelial hepatocytes do not secrete a continuous basal lamina but are able to interact with the endothelium of the sinusoids without direct contact via shared basal lamina proteins. The vascular perfusion and generated shear stress through the developing liver induces the proliferation of hepatocytes both in vivo and in vitro ( , ). Specific white blood cells, Kupffer cells, migrate later into the liver sinusoids. The usual functions of the liver in the production of plasma proteins and metabolism of nutrients is undertaken by the placenta; fetal hepatocytes are glycolytic and have low mitochondrial activity.
After stage 19, EryD cells (definitive erythrocytes), part of the second wave of haemopoiesis, are seen within the liver; their terminal maturation by enucleation occurs from postfertilization week 11 ( ) ( Ch. 13 ). The third wave of erythrocyte production, from haemopoietic stem cells in a number of regions (including the placental stroma and aorta-gonad-mesonephros region), seeds precursor cells to the liver, thymus and bone marrow, and subsequently give rise to all blood lineages. Although the liver has been considered a main site of haemopoiesis, a study at 15–16 postmenstrual weeks found that fewer lymphocytes were present in the liver than in abdominal lymph nodes ( ). In a comparison of adult and fetal patterns of gene expression in the liver, haemopoietic genes had low expression at 20–22 postmenstrual weeks, perhaps because by this time blood cell production is established in the bone marrow ( ).
At the end of the first trimester the liver almost fills the abdominal cavity, and its left lobe is nearly as large as its right (see Figs 23.14D–E and Figs 23.15B–E ). It remains relatively larger than in the adult throughout fetal life. The increase in fetal liver volume is linear between 18–30 postmenstrual weeks, with no sex differences. In diabetic mothers, fetal liver volume is increased by 20% or more, and it is also enlarged in fetuses with trisomy 21. In cases of fetal growth restriction, liver volume is decreased ( ).
Development of intrahepatic biliary ducts
The development of the intrahepatic biliary ducts follows the branching pattern of the portal vein radicles ( ). The cranial hepatic diverticulum gives rise to the liver hepatoblasts, the intrahepatic large bile ducts (right and left hepatic ducts, segmental ducts, area ducts and their first branches) and the small bile ducts (septal bile ducts, interlobular ducts and bile ductules). The portal and hepatic veins arise together from the vitelline veins. Early in development, the accumulation of mesenchyme around these veins is similar, whereas later mesenchyme increases around the portal veins; this accumulation is a prerequisite for bile duct development. Primitive hepatoblasts surround the portal vein branches and associated mesenchyme, and form a sleeve of cells termed the ductal plate. Individual cells of the ductal plate are termed cholangiocytes. Local hepatoblasts that are adjacent to the cholangiocytes arrange themselves to delineate a bile duct lumen and then also switch to a cholangiocyte lineage ( ). As the bile ducts develop, angiogenic mesenchymal cells form blood vessels that connect to the hepatic artery from postfertilization week 10. Thus, the portal triads are patterned by the portal vein radicles, which initially induce bile duct formation and then artery formation. The development of the biliary system extends from the hilum to the periphery. Anomalies of the biliary tree are associated with abnormalities of the branching pattern of the portal vein. The developing bile ducts remain patent throughout development ( ).
Development of extrahepatic biliary ducts
The caudal part of the hepatic endodermal diverticulum forms the extrahepatic biliary system, the common hepatic duct, gallbladder, cystic duct and common bile duct.
The bile duct, which originated from the ventral wall of the foregut (now duodenum), migrates with the ventral pancreatic bud, first to the right and then dorsomedially into the dorsal mesoduodenum. The right and left hepatic ducts arise from the cranial end of the common hepatic duct from postfertilization week 12.
Liver and biliary ducts at birth
In the neonate, the liver constitutes 4% of the body weight, compared to 2.5–3.5% in adults. It is in contact with the greater part of the respiratory diaphragm and extends below the costal arch anteriorly, and, in some cases, to within 1 cm of the iliac crest posteriorly. The left lobe covers much of the anterior surface of the stomach and constitutes nearly one-third of the liver ( Fig. 23.14A ). Fetal liver haemopoiesis ceases before birth, whereas enzymatic and synthetic functions are not completely mature at birth. Hepatocytes remain a heterogeneous population with different gene expressions and metabolic functions within different hepatic lobule locations: metabolic zonation becomes fully established after birth ( ).
In the neonate, the gallbladder has a smaller peritoneal surface than in the adult, and its fundus often does not extend to the liver margin. It is generally embedded in the liver and, in some cases, may be covered by bands of liver. After the second year, the gallbladder assumes the relative size it has in the adult. Normal sonographic measurements of liver and biliary ducts for neonates and infants is given in .
Atresia of the extrahepatic bile ducts in neonates occurs alone or in conjunction with a range of other anomalies, including situs inversus, malrotation, polysplenia and cardiac defects. In such cases, the intrahepatic bile ducts have a mature tubular shape but also show features of ductal plate malformation. Biliary atresia is seen more commonly in males ( ). Elevated bile acids in infants with biliary atresia has been reported and that postnatal biliary duct inflammatory process may be involved ( ).
Midgut
The midgut forms the third and fourth parts of the duodenum, jejunum, ileum and two-thirds of the way along the transverse colon; its development produces most of the small, and a portion of the large, intestine. In amniote embryos the midgut, which is connected to a narrowing vitelline intestinal duct to the yolk sac, forms a loop which projects away from the body ventrally, with a proximal cranial limb and a distal caudal limb; in mammals it enters the extraembryonic coelom. The usual explanation for this movement is that rotation of the loop can only occur out of the abdominal cavity, however, studies have shown that biomechanical transduction may promote gut lengthening, and suggest that the formation of the complex secondary and tertiary loops are controlled by genetic regulation. Experimental studies in chick embryo have indicated that the mechanical tension transmitted by the lengthening vitelline duct and the arteries passing to it along the dorsal mesentery, drive the proliferation and elongation of the midgut loop. In the absence of tension gut did not grow, i.e. there was no increase in volume or cell number ( ). The differential contribution of the endodermal core, the surrounding mesenchyme, or the outer coelomic epithelial layer which is continuous with the dorsal mesentery, remains to be elucidated.
In human embryos at stages 10–11 the midgut extends from the cranial to the caudal intestinal portals and communicates directly with the yolk sac over its entire length: it has a dorsal wall, but the lateral walls have not yet formed. By stage 12 the connection with the yolk sac has narrowed, such that the midgut has ventral walls cranially and caudally. This connection is reduced to a yolk stalk containing the vitello-intestinal duct during stage 13, at which time the yolk sac appears as a sphere in front of the embryo. Dorsal to the midgut, the splanchnopleuric coelomic epithelia converge, and form the dorsal mesentery with intervening mesenchyme. Ventrolaterally, the intraembryonic coelom is in wide communication with the extraembryonic coelom. At stage 14 the midgut has increased in length more than the axial length of the embryonic body and, with elongation of the dorsal mesentery, it bulges ventrally, deviating from the median plane (see Fig. 21.3 ).
The following description focuses on the movements of the elongating endodermal epithelial tube, surrounding splanchnopleuric mesenchyme and outer coelomic epithelium. For the later consequences of these movements, focusing on the coelomic epithelium and the fates of the elongating mesenteries relative to the dorsal wall of the developing peritoneal cavity, see p. 338 . There is consequently some repetition in these two accounts.
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